Sustained release parenteral formulations of buprenorphine

ABSTRACT

An oil-in-water buprenorphine formulation including buprenorphine and a surfactant that emulsifies the buprenorphine in oil, wherein the drug release is controlled by varying the oil concentration and/or pH. A buprenorphine aqueous suspension formulation including a free base buprenorphine and a suspension stabilizer. A buprenorphine oil formulation including a buprenorphine salt suspended in a pharmaceutically acceptable oil. Methods of providing sustained release of buprenorphine over a period of time.

CROSS REFERENCE SECTION TO RELATED APPLICATIONS

This application claims priority to U.S. application Ser. No.60/892.077. filed Feb. 28, 2007, and is incorporated herein by referencein its entirety

FIELD OF INVENTION

The present invention relates to sustained release pharmaceuticalcomposition formulations and related methods. More specifically, thepresent invention is directed towards sustained release injectableformulations of buprenorphine.

BACKGROUND ART

Buprenorphine is a semi-synthetic opioid analgesic with mixedagonist-antagonist properties. Besides being 20-40 times more potentthan morphine, one of its main advantages is that the dose does not needto be increased during chronic administration. Buprenorphine can be invarious forms such as sublingual tablets (0.2 mg) for the treatment ofmoderate, severe acute, and chronic pain, or as a pre-operativemedication. Sublingual tablets containing 0.4, 2 and 8 mg of the drugare used for the treatment of opioid addiction. Alternatively, it isavailable as an injection (0.3 mg/mL) for intravenous (hereinafter,“IV”), intramuscular (hereinafter, “IM”), intrathecal, and epiduraladministration as an analgesia in cases of severe acute pain and as apre-medication. Recommended doses are 200-600 μg by IV or IM injectionevery six to eight hours, 30-45 μg intrathecally or 100-300 μgepidurally every six to twelve hours or 400 μg sublingually every six toeight hours (R. C. Heel, R. N. Brogden, T. M. Speight and G. S. Avery.Drugs 17 (1979) 81-110; S. E. Robinson, CNS Drug Rev. 8 (2000) 377: P.J. Hoskin. G. W. Hanks. Drugs 30 (1991) 326: T. M. Tzschentke,Psychopharmacology 161 (2002) 1).

The prior art includes various references disclosing injectableslow-release formulations. For example, U.S. Pat. No. 6,495,155discloses an injectable slow-release partial opioid agonist and/oropioid antagonist formulation in a poly (D, L-lactide) excipient with asmall amount of residual ethyl acetate. The microparticles are under 125μm in diameter and can be readily injected intramuscularly to provide atleast about 0.5 ng/ml of drug over an extended period of time (28-60days). The formulations are provided for use in the treatment ofalcoholics and heroin addicts. Additionally, a subcutaneous depotproduct (Norvex™) exists wherein buprenorphine microcapsules consistingof buprenorphine base and biodegradable PLA-PGA polymer are disclosed(B.-F. X. Sobel et al. Drug and Alcohol Dependence 73 (2004) 11).Moreover, there are buprenorphine transdermal delivery systems (TDS)(e.g., Transtec™), formulated as a matrix patch and licensed for thetreatment of moderate to severe cancer pain and severe pain notresponding to non-opioid analgesics. The patch is available in threestrengths delivering 35, 52.5 or 70 mcg/hr over seventy-two hours (R.Sittl et al., Clin. Ther. January 2003; 25(1): 150; Expert Rev.Neurother. May 2005; 5(3): 315).

A study has found that buprenorphine propionate when prepared as a depothad a long-lasting analgesic effect, which was 7.5-fold longer than thetraditional dosage form of buprenorphine in saline preparation,following IM injection in rats. The long lasting effect of IM depot ofbuprenorphine propionate is reported to be due to a slow release ofbuprenorphine propionate from its oil vehicle (S.-Y. Liu et al., J.Chromatogr B 818 (2005) 233; J. J. Wang, Patent of the Republic ofChina, No. 1226830 (2005)). They have subsequently synthesized andformulated other depots of buprenorphine esters, buprenorphine enanthateand decanoate. The buprenorphine decanoate in oil produced a 14-foldlonger duration of action than buprenorphine HCl in saline (K. -S. Liuet. al. Anesth Analg 2006; 102; 1445).

U.S. Pat. No. 6,335,035 discloses the preparation of a sustained releasedelivery system using a polymer matrix containing a drug for use intreating acute or chronic conditions. The drug is dispersed within apolymer matrix solubilized or suspended in a polymer matrix. The polymermatrix is composed of a highly negative charged polymer material such aspolysulfated glucosoglycans, glycosaminoglycans, mucopolysaccharides andmixtures thereof, and a nonionic polymer such as carboxymethylcellulosesodium, hydroxyethyl cellulose, hydroxypropyl cellulose, and mixturesthereof.

U.S. Pat. No. 4,613,505 discloses a fat emulsion specific to an ester offlurbiprofen to provide an orally and parenterally administrable,particularly intravenously administrable, preparation having anexcellent anti-inflammatory, analgesic and antipyretic activity and onlya minor side effect.

U.S. Pat. No. 6,197,344 discloses controlled release suspensionformulations of the opioid analgesic, butorphanol and the use of suchformulations for pain management over periods of time ranging from 12 to24 hours. South African Patent Application 91/4549 is referenced, whichdiscloses microsphere pharmaceutical formulations and the use of such indelivering therapeutic agents. Pharmaceutically active substances thatcan be administered using such microspheres are tranquilizers,anti-emetics, vasodilators, antihistaminics, steroids and analgesics.

Finally, slow release emulsions containing either morphine base ormorphine hydrochloride were prepared and formulated by Collier et. al.The preparation consists of suspending 150 mg of morphine base in 0.75mL of an emulsifying agent, mannide monooleate (“Aracel A”), and 4.25 mLof light liquid paraffin. This oily phase was emulsified with 5 mL of0.9% w/v NaCl in water (H. O. J. Collier et.al., Nature Vol 237 May 26,1972).

Although the use of emulsions and suspensions for drug delivery is notuncommon and has been used in other analgesics, there are also problemsassociated with them. However, sustained release injectablebuprenorphine formulations that exist in the prior art utilize morecomplicated systems such as microparticles or prodrugs in an oilvehicle. More particularly, the manufacturing of microparticles involvesutilizing complex and costly processes with the use of organic solvents.Additionally, it can be difficult to achieve sterility of microparticlesand other oil solutions because terminal sterilization is not alwayspossible. In addition to these disadvantages, it is difficult toappropriately control the release of a drug such as buprenorphine in aninjectable dosage form in order to achieve the desired onset andduration of analgesic effects in the target species. Accordingly, therecontinues to be a need for reasonably simpler and more practicalformulations for sustained release of buprenorphine.

SUMMARY OF THE INVENTION

The present invention provides, in one embodiment, an oil-in-waterbuprenorphine formulation including buprenorphine and a surfactant thatemulsifies the buprenorphine in oil, wherein the buprenorphine releaseis controlled by varying the oil concentration and/or pH of theemulsion. Additionally, the present invention provides an aqueoussuspension formulation including free base buprenorphine and asuspension stabilizer. Further, the present invention provides an oilformulation including buprenorphine salt suspended in a pharmaceuticallyacceptable oil. The present invention also provides various methods ofcontrolling the release of buprenorphine over a period of time throughadministration of the various formulations. In addition, the presentinvention provides methods of manufacturing the various formulationsthereof.

DESCRIPTION OF DRAWINGS

Other advantages of the present invention will be readily appreciated,as the same becomes better understood by reference to the followingdetailed description when considered in connection with the accompanyingdrawings, wherein:

FIG. 1 is a chart demonstrating a buprenorphine release profile fromIntralipid emulsions into NS;

FIG. 2 is a chart demonstrating buprenorphine release profile fromsuspensions at various pH values into NS;

FIG. 3 is a chart of a buprenorphine blood concentration-time profileafter subcutaneous administration of solution and suspensionformulations in rats; and

FIG. 4 is a chart of a buprenorphine blood concentration-time profileafter subcutaneous administration of emulsions containing 0.8 mg/ml ofbuprenorphine with various concentrations of Intralipid® in rats.

DETAILED DESCRIPTION OF THE INVENTION

Generally, the present invention is directed towards formulations andrelated methods of preparation and manufacturing of a sustained releaseinjectable formulation of buprenorphine. More specifically, theformulation can be an oil-in-water emulsion, an aqueous suspension ofthe buprenorphine free base, or an oil suspension of the buprenorphinesalt, wherein any of the formulations can include or exclude apreservative. The present invention also relates to the use of suchformulation for controlled release of buprenorphine over a period oftwelve to forty-eight hours for human or veterinary medicine.

The present invention provides numerous advantages over the prior art.The present invention provides a simpler more practical, and inexpensivemethod of preparing formulations that can achieve sustained release ofbuprenorphine. The present invention provides flexibility in controllingthe release of buprenorphine by varying the different factors thatcontrol the release. These factors include, but are not limited to,lipid concentration, pH, particle or globule size, and buprenorphineconcentration. Further, extensive data and excellent tissuebiocompatibility have been demonstrated for emulsions as a drug deliverysystem. The administration of an emulsion subcutaneously orintramuscularly is straightforward without the need for reconstitutionas with microparticles. Owing to the relatively low viscosity of anemulsion, the use of smaller needle size is more feasible with anemulsion than an oil solution.

As an application, for example, in the horse, the onset of action isapproximately fifteen minutes after IV dosing of buprenorphine. The peakeffect occurs in thirty to forty minutes and the duration of action canlast up to eight hours. The disposition of buprenorphine (10 μg/kg)after intravenous and intramuscular as well as oral muccosal route hasbeen reported in cats. Based on changes in thermal threshold, i.m. dosesof 10 μg/kg resulted in a slow onset (two hours) of analgesia, but onceestablished, this lasted at least six hours. Use of the sustainedrelease formulation could prolong the duration of action (12 to 48hours) in these species.

As used herein, the term “buprenorphine” means an opioid drug withpartial agonist and antagonist actions. It can be in various formsincluding, but not limited to, a free base form or as a salt. The saltform can be buprenorphine HCl or any other similar salts known to thoseof skill in the art.

The present invention has numerous embodiments. One embodiment of thepresent invention is an oil-in-water buprenorphine formulation includingbuprenorphine and a surfactant that emulsifies the buprenorphine in oil,wherein the release is controlled by varying the oil concentrationand/or pH. The buprenorphine can be a free base or a salt. Further, thesurfactant can be, but is not limited to, synthetic non-ionicsurfactants, polypropylene polyethylene block copolymers, phosphatides,egg phosphatide, combinations thereof, and any other similar surfactantsknown to those of skill in the art. In this embodiment, thebuprenorphine can be dissolved in a water immiscible solvent including,but not limited to, vegetable oil, soybean oil, safflower oil,cottonseed oil, corn oil, sunflower oil, arachis oil, castor oil, oliveoil, ester of a medium or long chain fatty acid such as a mono-, di-, ortriglyceride, ethyl oleate, isopropyl myristate, polyoxyl hydrogenatedcastor oil, combinations thereof, and other similar solvents known tothose of skill in the art. Moreover, the formulation can optionallyinclude glycerol, which can cause the formulation to be isotonic. Thecomposition can also include, but is not limited to, pH adjusting agentsincluding, but not limited to, sodium hydroxide, and a pharmaceuticallyacceptable buffer system such as, but not limited to, sodium citrate andsodium phosphate. Preferably, the pH is adjusted to be between about 6to about 9. Further, the formulation can include a preservative such as,but not limited to, benzyl alcohol, EDTA, combinations thereof, and anyother similar preservative known to those of skill in the art. Finally,the remaining formulation is water.

Another embodiment is directed towards a buprenorphine aqueousformulation where the free base buprenorphine is suspended in an aqueousmedium. In this embodiment, the free base buprenorphine can be formed bythe addition of an alkali metal salt such as, but not limited to, NaOHto a buprenorphine salt solution. Further, a suspending agent can beadded, but is not limited to, polyvinyl pyrrolidone (PVP), sodiumcarboxymethylcellulose (Na-CMC), dextran, and other similar agents knownto those of skill in the art. Alternatively, the aqueous suspension canbe formulated by dispersing the buprenorphine free base into thesuspending agent solution and mixing with a high shear homogenizer.Buprenorphine has a pKa of about 8.24. The solubility of thebuprenorphine is inversely proportional to pH over the pH range of about6.0 to 8.0 and this can be utilized to control the release. The initialrate of release of the drug is higher at low pH levels. The compositioncan further include a surfactant such as, but not limited to, PluronicF127, polysorbates and other surfactants acceptable for parenteraladministration. Additionally, the formulation can include additionalsubstances such as a buffer including, but not limited to, sodiumcitrate and sodium phosphate, and other similar buffers known to thoseof skill in the art. Further, the formulation can include a preservativesuch as, but not limited to, benzyl alcohol, methyl paraben, propylparaben, combinations thereof, and any other similar preservative knownto those of skill in the art.

A further embodiment is directed towards a buprenorphine oil formulationwhere a buprenorphine salt is suspended in a pharmaceutically acceptableoil. The buprenorphine salt can be, but is not limited to, buprenorphineHCl. Further, the pharmaceutically acceptable oil includes, but is notlimited to, cottonseed oil, corn oil, peanut oil, soybean oil,combinations thereof and other similar oils known to those of skill inthe art. The composition can further include a suspending agent such asa sorbitan fatty acid hexitan ester.

The present invention also provides methods of providing sustainedrelease of buprenorphine over a period of time by administering any ofthe formulations of the present invention.

The above discussion provides a factual basis for the use of the presentinvention described herein. The present invention is further illustratedby the following non-limiting examples.

EXAMPLES Example One Preparation of Buprenorphine Formulations

Preparation of 1.5 mg/ml Biprenorphine in 30% Intralipid® Oil-in-WaterEmulsion at pH 8.0

7.5 mg (free base equivalent) of buprenorphine HCl was dissolved inethanol and sterile filtered into a vial. The ethanol was evaporated bypurging with nitrogen. 4.7 mL of 30% Intralipid® fat IV emulsion wasadded into the vial containing the sterile buprenorphine HCl. The vialwas shaken vigorously for about thirty seconds to disperse thebuprenorphine HCl in the Intralipid. The vial was stirred at a highspeed or at about 1000 rpm on a magnetic stirrer at room temperature fortwo hours or more. Once the buprenorphine has all dissolved, 0.18 ml of0.1 N NaOH (sterile filtered) was injected into the vial containing 7.5mg buprenorphine and Intralipid®. The vial was stirred at a high speedor at about 1000 rpm on a magnetic stirrer at room temperature for twohours or more prior to administration.

Preparation of 0.8 mg/mL of Buprenorphine Aqueous Suspension at pH 6.8

A solution of 1% PVP K-30 and 1.4% glycerin was prepared. For example,2.5 g PVP and 3.5 g glycerin were added to a 250 ml volumetric flask andq.s with water. 4.5 mg of buprenorphine HCl was accurately weighed in avial and 5 mL of the PVP and glycerin solution was added. The solutionwas stirred until dissolved. Sterile filtering of the solution thenoccurred. 0.05 ml of sterile 0.1 N NaOH was added to the vial containing0.8 mg/ml of buprenorphine (free base equivalent) while the vial wasstirring on a magnetic stirrer. The vial was stirred at 1000 rpm (fastsetting) on the magnetic stirrer at room temperature for three hoursprior to administration.

In vitro Release Studies

Buprenorphine HCl Emulsion Preparation

Buprenorphine HCl (˜2.4 mg) was weighed, dissolved in 3 mL of 5%, 10% or20% Intralipid emulsion to reach a final concentration of ˜0.5 mg/mL.The pH of buprenorphine emulsions were ˜5.0 without pH adjustment. ThepH was adjusted to about pH 8.0 with dilute NaOH. Both emulsions withdifferent pHs were evaluated for their release characteristics.

Buprenorphine HCl Suspension Preparation

Buprenorphine HCl (˜11 mg) was weighed, dissolved in distilled water andmade up to 10 mL in a volumetric flask to reach a final concentration of˜1.1 mg/mL. A 3 mL aliquot of this solution was used to prepare asuspension by adjusting the solution to various pH values (6.6, 6.8,7.0) by adding dilute NaOH. A portion of the buprenorphine HCl wasprecipitated as the free base and the remaining portion was dissolved asthe hydrochloride salt form.

Release Studies

A dialysis tubing with a length of 5 to 10 cm (Spectrum, 4 mm diameter,8,000 MWCO) was used to hold emulsion, suspension or solutionformulations containing buprenorphine. The tubing was first wetted indistilled water and the appropriate amount of formulations (˜0.5 mL) wasintroduced into the tubing with a syringe. The dialysis tubing was thensealed with plastic clamps to prevent leakage and was placed into 20 mLof release medium in a covered Petri dish. The release solution wasstirred magnetically. At appropriate time intervals. 5 mL samples werewithdrawn and replaced with fresh medium. The release samples wereanalyzed for buprenorphine by HPLC.

HPLC Analysis

The mobile phase was prepared as described in USP 24 (p. 258). Ammoniumacetate (1 g) was dissolved in 100 mL of distilled water to obtain a 1%solution. To this solution, a 100 μL aliquot of glacial acetic acid wasadded and this buffer was then added to 600 mL of HPLC grade methanoland the solution was filtered through a 0.22 μm filter and de-gassed.The mobile phase flow rate was 1 mL/min with an injection volume of 100μL. The detection wavelength was either 250 nm or 288 nm.

The HPLC system was a Shimadzu system including a LC-10AT pump, SIL-10ADauto injector, SPD-10A UV-Visible detector, and SCL-10A systemcontroller with Shimadzu Class VP software (ver. 4.3) for system controland data acquisition. The column was a Waters SymmetryShield™ RP18, 5 μmparticle size, 3.9*100 mm, with a C18 guard column.

Release Studies from Intralipid Emulsions Using Dialysis Tubing

Buprenorphine release data from Intralipid emulsions at different pHvalues are tabulated in Table 1 and plotted in FIG. 1.

TABLE 1 Buprenorphine release profile from Intralipid emulsions into NS.% Released 5% 10% 20% 5% 10% 20% Time Intralipid Intralipid IntralipidIntralipid Intralipid Intralipid (hr) pH 5.02 pH 5.30 pH 5.79 pH 7.92 pH8.06 pH 7.81 0.5 15.7 8.5 5.1 3.4 2.5 2.8 1 25.7 15.8 8.5 4.9 4.1 3.7 235.3 23.0 15.3 7.9 7.1 4.7 4 46.7 34.0 22.7 13.4 10.7 6.9 6 48.5 35.730.8 20.6 14.6 10.6 8 — — — 23.8 19.7 11.3 11 56.3 43.0 40.0 — — — 2454.2 43.0 46.6 43.1 42.0 34.7Release Studies from Various pH Suspensions Using Dialysis Tubing

Buprenorphine release data from suspensions with different pH values aretabulated in Table 2 and plotted in FIG. 2.

TABLE 2 Buprenorphine release profile from suspension with various pHvalues into NS % Released Time (hr) pH 6.6 pH 6.8 pH 7.0 0.5 10.4 8.42.8 1 18.5 15.2 4.4 2 25.2 22.6 6.1 4 31.7 28.5 8.5 6 36.9 30.5 9.7 1138.7 34.9 16.2 24 29.7 27.4 17.2

Example Two In Vivo Subcutaneous Administration of Emulsion andSuspension Formulations in Rats Buprenorphine HCl Solution Preparation

Buprenorphine HCl (˜4.3 mg) was weighed, dissolved in distilled waterand made up to 5 mL in a volumetric flask to reach a final concentrationof ˜0.8 mg/mL buprenorphine free base equivalent.

Buprenorphine HCl Emulsion Preparation

Buprenorphine HCl (˜2.58 mg) was weighed, dissolved in 3 mL of 5%, 10%or 20% Intralipid emulsion to reach a final concentration of ˜0.8 mg/mLbuprenorphine free base equivalent. The pH was adjusted to ˜8.0 with0.1N NaOH.

Buprenorphine HCl Suspension Preparation

Polyvinylpyrrolidone (˜0.25 g, PVP K-30) was weighed, dissolved in waterand made up to 25 mL in a volumetric flask to reach a finalconcentration of 1%. Buprenorphine HCl (˜8.61 mg) was weighed anddissolved in 10 mL of 1% PVP solution to reach a final concentration of˜0.8 mg/mL buprenorphine free base equivalent. An aliquot (3 mL) of thissolution was used to prepare the suspension in 1% PVP by raising the pHto 6.8 using 0.1N NaOH.

In vivo Studies

Three, 250-300 g, male Sprague-Dawley rats were tested for eachformulation. Animals were obtained from the vendor on a weekly basis,and each group of animals was allowed to acclimate to the housingfacility for at least 24 hours. Animals were allowed full access to foodand water before and during the experiment, and each animal was weighedprior to formulation administration (Table 3).

A 0.3 mL, 29 gauge insulin syringe was filled with formulation (50 μl)using aseptic technique. The skin at the nape of the rates neck waslifted and the needle was inserted under the skin, parallel to the longaxis of the skin fold. Approximately 2-3 min prior to each samplingtime, the animal was placed into a plexiglass rat restrainer (HarvardBioscience, Holliston, Mass.), keeping the tail free. To dilate the tailvein for sampling, the tail was placed briefly (˜10 sec) into warm water(70-80° C.) and was then kept warm by placing it ˜1 cm beneath a 100Wlight bulb for one minute. Precautions were taken to ensure that theanimal was not burned during these procedures. Blood was collected fromthe tail vein using a heparinized, 23G butterfly needle. The tubing fromthe butterfly needle was trimmed to ˜1 cm from the hub to reduce thedead volume. Approximately 8-10 drops of blood were collected into 1.5ml polypropylene centrifuge tube that had been previously rinsed withheparinized EIA buffer (see below). From this sample, 50 μl of wholeblood was transferred to another vial containing 200 μl of heparinized(10,000 U/L) EIA buffer (1:5 dilution). Both the remaining whole bloodand diluted blood samples were immediately frozen using a dryice/acetone bath and then stored at −70° C until analysis.

ELISA Analysis:

Buprenorphine ELISA kits were obtained from Neogen Corp (Lexington, Ky.)and used as directed. Briefly, 20 μl of sample (1:5 dilution of wholeblood, calibration standard, or Neogen-supplied control in EIA buffer)was pipetted into the well of a 96 well plate. Drug-enzyme (horseradishperoxidase) conjugate (180× dilution in EIA buffer) was placed into eachwell, the cover supplied was placed on top of the plate and the systemwas shaken for 45 min at ambient temperature on a microplate shaker(Precision Scientific. Chicago, Ill.). The liquid was removed from theplate by inversion, and 300 μl of wash buffer (1:10 dilution in EIAbuffer) was added into each well. The plate was inverted to remove thebuffer and the washing step was repeated two additional times. Followingthe removal of the final wash buffer, 150 μl of K-Blue substrate(3′,3′,5,5′ tetramethylbenzidine; hydrogen peroxide) was added to eachwell and the system was placed on a microplate shaker at ambienttemperature for thirty minutes. Red Stop Solution (50 μl) was added toeach well, the plate was gently mixed and the absorbance read at 650 nm(Molecular Devices, Model 384, Union City, Calif.). Calibrationstandards were prepared using buprenorphine HCl (Diosynth, lot #L00025491). A calibration curve was prepared for each experiment/plateby plotting the optical density readings versus buprenorphineconcentrations from the standards included on the plate. A calibrationcurve was established with these results using regression analysis. Thelimit of quantitation used for all assays was 0.8 ng/mL.

Bioavailability comparisons between formulations can be made using thearea under the plasma concentration-time curve. The AUC was calculatedby summing the areas of any two adjacent time points by trapezoidalrule. No extrapolation beyond the final collection time was made.

Results:

The blood concentration-time profiles following subcutaneousadministration of long-acting buprenorphine formulations are shown inFIGS. 3 and 4. The pharmacokinetic parameters (C_(max), t_(max), AUC)derived from the mean (N.D.=0) concentration-time profiles are listed inTable 4.

Two different doses of buprenorphine were administered as solutions. 15μg (as 0.3 mg/mL) and 40 μg (as 0.8 mg/ml). As expected, the absorptionfrom the solution formulation (FIG. 3) was rapid, with a t_(max) of ˜15min. The C_(max) values for each were nearly dose-proportional (2.3-foldcompared to an expected 2.7-fold increase in C_(max) for the higherdose, Table 4). Both formulations were cleared rapidly, with thegreatest differences in blood concentrations observed in the first hour.Buprenorphine could not be detected in the blood after ˜8 hours foreither dose. The AUC values were not dose-proportional, however, and thelow AUC measured for the 40 μg dose may be reflective of the limit ofquantitation used for the assay.

The suspension (0.8 mg/ml) gave lower but more prolonged concentrationsof buprenorphine in the blood (FIG. 3). Measurable buprenorphineconcentrations were detected for up to 56 hours in two of the ratstested. The t_(max) for the suspension occurred at the first samplingtime (15 min), and the blood concentration (3.2 ng/mL) at this time wassimilar to the concentration measured at 56 hours (1.25 ng/ml) (Table4), indicating that the suspension provided a low, but sustained releaseof buprenorphine for at least two days.

Significant differences were seen in the performance of the emulsionformulations with varying concentrations of Intralipid® (FIG. 4). Thelowest Intralipid® concentration (10%) gave similar results as thesolution formulation while the 20% and 30% Intralipid concentrationsboth showed lower, more prolonged buprenorphine concentrations. As withthe solution formulation, measurable levels of buprenorphine were notdetected after 8 hours for the 10% Intralipid® emulsion. At least oneanimal had a detectable concentration of buprenorphine at 12 hours withthe 20% Intralipid® formulation, and one animal had detectable levelsfor up to 26 hours with the 30% Intralipid® formulation. The t_(max) waslonger (4 hr) for the 30% Intralipid® formulation as compared to the 10%and 20% concentrations (1 hr and 2 hr, respectively). The AUC for the30% Intralipid® formulation was 1.8-fold greater than with the 20%formulation, while the 10% formulation had the largest AUC due to theextremely high buprenorphine plasma concentrations measured during thefirst four hours following administration. Based on these data. itappears that the 30% Intralipid® formulation has slightly bettersustained action than the other formulations tested.

TABLE 3 Weight of each animal prior to dosing Rat 1 Rat 2 Rat 3 GroupWeight (g) Weight (g) Weight (g) Solution (0.3 mg/ml) 320 330 322Solution (0.8 mg/ml) 325 321 301 Emulsion (10% 328 330 329 Intralipid)Emulsion (20% 338 354 353 Intralipid) Emulsion (30% 360 356 355Intralipid) Suspension (0.8 mg/ml) 320 310 309

TABLE 4 Pharmacokinetic parameters calculated from the bloodconcentration-time profiles of subcutaneously administered buprenorphineHCl formulations. Formulation C_(max) (ng/ml) T_(max) (hr) AUC (hr ·ng/ml) Solution (0.3 mg/ml) 4.87 0.25 13.64 Solution (0.8 mg/ml) 11.230.25 19.92 Emulsion (10% 13.77 1 59.60 Intralipid) Emulsion (20% 4.3 225.39 Intralipid) Emulsion (30% 4.12 4 44.86 Intralipid) Suspension (0.8mg/ml) 3.2 0.25 52.29

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents.

1. An oil-in-water buprenorphine formulation comprising buprenorphine:and a surfactant that emulsifies said buprenorphine in oil, whereincontrol of release of said buprenorphine is controlled by varying theoil concentration and/or pH.
 2. The formulation according to claim 1,wherein said buprenorphine is selected from the group consisting of afree base and a salt.
 3. The formulation according to claim 1, whereinsaid surfactant is selected from the group consisting of syntheticnon-ionic surfactants, polypropylene polyethylene block copolymers,phosphatides, egg phosphatide, polysorbates, other surfactantsacceptable for parenteral administration, and combinations thereof. 4.The formulation according to claim 1, wherein said buprenorphine isdissolved in a water immiscible solvent selected from the groupconsisting of vegetable oil, soybean oil, safflower oil cottonseed oil,corn oil, sunflower oil, arachis oil, castor oil, olive oil, ester of amedium or long chain fatty acid such as a mono- di-, or triglyceride,ethyl oleate, isopropyl myristate, polyoxyl hydrogenated castor oil, andcombinations thereof.
 5. The formulation according to claim 1 furthercomprising glycerol.
 6. The formulation according to claim 1 furthercomprising pH adjusting agents selected from the group consisting ofsodium hydroxide.
 7. The formulation according to claim 1 furthercomprising substances selected from the group consisting of a bufferfurther selected from the group consisting of sodium citrate and sodiumphosphate, and combinations thereof.
 8. The formulation according toclaim 1 further comprising preservatives selected from the groupconsisting of benzyl alcohol, EDTA, and combinations thereof.
 9. Abuprenorphine aqueous suspension formulation comprising free basebuprenorphine and a suspending agent.
 10. The formulation according toclaim 9, wherein said buprenorphine is a free base buprenorphine formedby the addition of an alkali metal salt selected from the groupconsisting of NaOH to buprenorphine salt.
 11. The formulation accordingto claim 9, wherein said suspending agent is selected from the groupconsisting of polyvinyl pyrrolidone (PVP) sodium carboxymethylcellulose,and dextran.
 12. The formulation according to claim 9, wherein thecomposition has a pH of from about 6 to about
 8. 13. The formulationaccording to claim 9, wherein said formulation further comprisessubstances selected from the group consisting of a buffer furtherselected from the group consisting of sodium citrate and sodiumphosphate, and combinations thereof.
 14. The formulation according toclaim 9 further comprising preservatives selected from the groupconsisting of benzyl alcohol, methyl paraben, propyl paraben, andcombinations thereof.
 15. The formulation according to claim 9, whereinsaid buprenorphine is a free base buprenorphine formed by dispersingsaid buprenorphine free base into the suspending agent solution andmixing the formulation with a high shear homogenizer.
 16. Abuprenorphine oil formulation comprising a buprenorphine salt suspendedin a pharmaceutically acceptable oil.
 17. The formulation according toclaim 15, wherein said buprenorphine salt is buprenorphine HCl.
 18. Theformulation according to claim 15, wherein said pharmaceuticallyacceptable oil is selected from the group consisting of cottonseed oil,corn oil, peanut oil, and soybean oil.
 19. The formulation according toclaim 15 further comprising a suspending agent as a sorbitan fatty acidhexitan ester.
 20. A method of providing sustained release ofbuprenorphine over a period of time by administering the formulationaccording to claims 1, 9, and 16.